1. Field of the Invention
This invention generally relates to formulations and methods of formulating cardiotonic phosphodiesterase (PDE) inhibitors. Of particular interest are those compounds which are (2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolinyl)oxyalkylamides.
2. Related Art
Exemplary compounds of this general class are known in the prior art. In particular, U.S. Pat. No. 4,490,371 and its continuation U.S. Pat. No. 4,551,459 disclose a series of (2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolinyl)-oxyalkylamides as cyclic AMP phosphodiesterase inhibitors useful as anti-thrombotic agents and the like in mammals, and also having inotropic and anti-metastatic activities. The U.S. Pat. No. 4,490,371, as well as U.S. Pat. No. 4,551,459 (issuing from Ser. No. 599,858), and U.S. Pat. No. 4,663,320, (issuing from Ser. No. 744,100), assigned to the assignee of the present invention, are hereby fully incorporated into this patent application by reference.
In general, phosphodiesterase inhibitors are known to have limited solubility and stability in water. In particular, it has been found that with the (2-oxo-1,2,3,5-tetrahydroimidazo-[2,1-b]-quinazolinyl)-oxalylamides of U.S. Pat. Nos. 4,490,371 and 4,551,459, cosolvent systems of varying compositions (e.g., in the range of 10 to 50% ethanol, polyethylene glycol or the like) improve the solubility only slightly, and increase the incidence of local irritation in parenteral administration. In order to most conveniently administer the disclosed compounds intravenously, a need exists to develop a formulation that will enhance their solubility in water, while providing sufficient stability to maintain a commercially acceptable shelf life of at least two years.